{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T18:25:21Z","timestamp":1787077521330,"version":"build-2736575974"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020768","name":"University of Utah Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020768","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000964","name":"Arthritis National Research Foundation","doi-asserted-by":"publisher","award":["MJJ  707634"],"award-info":[{"award-number":["MJJ  707634"]}],"id":[{"id":"10.13039\/100000964","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003393","name":"L. J. Skaggs and Mary C. Skaggs Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003393","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Osteoarthritis (OA) is a disease characterized by loss of joint space, degeneration of cartilage at articular surfaces, remodeling of bone and other joint tissues, low-grade inflammation, and pain. It is a leading cause of disability in the aging population. We do not have effective disease-modifying drugs because we lack a comprehensive understanding of the genetic pathways underlying OA development. Our recent work demonstrated that dominant hypermorphic mutations in the osmotic stress sensing kinase, WNK2, are associated with OA susceptibility. To explore WNK2 inhibition as a potential disease-modifying osteoarthritis drug, we identified a WNK2 inhibitor by using a combination of computational and experimental approaches. We used AlphaFold2 to model the WNK2 kinase domain with high confidence (pLDDT score &amp;gt;90), enabling virtual screening of 4.8 million compounds in the ZINC database. Structure-based filtering prioritized 53 candidates interacting with WNK2-specific residues Glu245 and Glu249, with binding energies from \u22124 to \u22128 kcal\/mol. M04, (1-(6-((3,5-bis(trifluoromethyl)benzyl)(methyl)amino)pyrimidin-4-yl)pyrrolidin-2-yl)methanol, emerged as a partially selective WNK2 inhibitor with minimal cytotoxicity in human T\/C-28a2 chondrocyte cells (cell viability IC50 = 416 \u03bcM). M04 inhibited IL1\u03b2-mediated proinflammatory gene expression in primary human chondrocytes. RNaseq analysis comparing M04 vs a pan-WNK inhibitor in primary human chondrocytes indicated that M04 was a more effective at reducing expression of IL1\u03b2-induced OA-associated pathways. Further studies indicated the R-enantiomer is the active form of the molecule. These findings position M04 as a promising lead for WNK2-targeted OA therapy, supporting further in vivo studies for optimization and validation.<\/jats:p>","DOI":"10.1021\/acsomega.6c04569","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T21:01:42Z","timestamp":1786136502000},"page":"48157-48172","source":"Crossref","is-referenced-by-count":0,"title":["Identification\nand Validation of a Novel WNK2 Inhibitor:\nA New Genetically Informed Target for Osteoarthritis Drug Development"],"prefix":"10.1021","volume":"11","author":[{"given":"Shivakumar R.","family":"Veerabhadraiah","sequence":"first","affiliation":[{"name":"University of Utah , , , ,","place":["Salt Lake City, Utah, United States, 84108"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ma","sequence":"additional","affiliation":[{"name":"University of Utah , , , ,","place":["Salt Lake City, Utah, United States, 84108"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subramanya","family":"Hegde","sequence":"additional","affiliation":[{"name":"University of Utah Therapeutics Accelerator Hub, University of Utah , , ,","place":["Salt Lake City, Utah, United States, 84112"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Stark","sequence":"additional","affiliation":[{"name":"University of Utah Therapeutics Accelerator Hub, University of Utah , , ,","place":["Salt Lake City, Utah, United States, 84112"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2702-9164","authenticated-orcid":true,"given":"Michael J.","family":"Jurynec","sequence":"additional","affiliation":[{"name":"University of Utah , , , ,","place":["Salt Lake City, Utah, United States, 84108"]},{"name":"University of Utah , , , ,","place":["Salt Lake City, Utah, United States, 84112"]},{"name":"University of Utah , , , ,","place":["Salt Lake City, Utah, United States, 84112"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026081811105179800_cit1","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis:\na disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis\nRheum."},{"key":"2026081811105179800_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.rdc.2012.10.004","article-title":"Epidemiology of osteoarthritis","volume":"39","author":"Neogi","year":"2013","journal-title":"Rheum Dis Clin\nNorth Am."},{"key":"2026081811105179800_cit3","doi-asserted-by":"publisher","first-page":"e633","DOI":"10.1016\/S2665-9913(20)30279-4","article-title":"Of mice\nand men: converging on a common molecular understanding of osteoarthritis","volume":"2","author":"Vincent","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"2026081811105179800_cit4","doi-asserted-by":"publisher","first-page":"R193","DOI":"10.1093\/hmg\/ddx302","article-title":"Pathways to\nunderstanding the genomic aetiology of osteoarthritis","volume":"26","author":"Cibrian Uhalte","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2026081811105179800_cit5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3899\/jrheum.150710","article-title":"The Genetic\nEpidemiological Landscape\nof Hip and Knee Osteoarthritis: Where Are We Now and Where Are We\nGoing?","volume":"43","author":"Zengini","year":"2016","journal-title":"J. Rheumatol."},{"key":"2026081811105179800_cit6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.30802\/AALAS-CM-21-000043","article-title":"Mouse Models\nof Osteoarthritis: A Summary of Models and Outcomes Assessment","volume":"72","author":"Drevet","year":"2022","journal-title":"Comp. Med."},{"key":"2026081811105179800_cit7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11926-015-0528-x","article-title":"Implementation\nof Functional Genomics for Bench-to-Bedside\nTransition in Osteoarthritis","volume":"17","author":"Ramos","year":"2015","journal-title":"Curr. Rheumatol.\nRep."},{"key":"2026081811105179800_cit8","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.molmed.2015.11.006","article-title":"Genetic Determinism of Primary Early-Onset Osteoarthritis","volume":"22","author":"Aury-Landas","year":"2016","journal-title":"Trends Mol. Med."},{"key":"2026081811105179800_cit9","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1002\/art.41520","article-title":"Familial Clustering\nof Erosive Hand Osteoarthritis in a Large Statewide\nCohort","volume":"73","author":"Kazmers","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"2026081811105179800_cit10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jhsa.2019.10.005","article-title":"Evaluation\nfor Kienbock Disease Familial Clustering: A Population-Based Cohort\nStudy","volume":"45","author":"Kazmers","year":"2020","journal-title":"J. Hand Surg. 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Genet."},{"key":"2026081811105179800_cit14","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1136\/ard-2022-223468","article-title":"Meta-analysis of erosive hand osteoarthritis identifies four common\nvariants that associate with relatively large effect","volume":"82","author":"Styrkarsdottir","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"2026081811105179800_cit15","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1136\/annrheumdis-2022-222497","article-title":"NOD\/RIPK2 signalling\npathway contributes to osteoarthritis susceptibility","volume":"81","author":"Jurynec","year":"2022","journal-title":"Ann. Rheum. 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Chem."},{"key":"2026081811105179800_cit19","doi-asserted-by":"publisher","first-page":"100795","DOI":"10.1016\/j.ocarto.2026.100795","article-title":"Familial clustering and physiological risk factors\nassociated with\nintervertebral disc degeneration in a large population-based cohort","volume":"8","author":"Rose","year":"2026","journal-title":"Osteoarthr Cartil. Open"},{"key":"2026081811105179800_cit20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2535302123","article-title":"Human pannexin mutations\nand their implications in erosive osteoarthritis","volume":"123","author":"Tang","year":"2026","journal-title":"Proc. Natl. Acad. Sci. U. S. 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J."},{"key":"2026081811105179800_cit24","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1126\/science.1062844","article-title":"Human hypertension caused\nby mutations in WNK kinases","volume":"293","author":"Wilson","year":"2001","journal-title":"Science"},{"key":"2026081811105179800_cit25","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/nchembio.2168","article-title":"Small-molecule WNK inhibition regulates cardiovascular\nand renal\nfunction","volume":"12","author":"Yamada","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"2026081811105179800_cit26","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1016\/j.cub.2022.01.056","article-title":"The opposing\nchloride cotransporters KCC and NKCC control locomotor activity in\nconstant light and during long days","volume":"32","author":"Eick","year":"2022","journal-title":"Curr. 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Revised estimates of the impact of\ngenetic support for drug mechanisms on the probability of drug approval","volume":"15","author":"King","year":"2019","journal-title":"PLoS Genet."},{"key":"2026081811105179800_cit30","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41586-024-07316-0","article-title":"Refining the impact\nof genetic evidence on clinical success","volume":"629","author":"Minikel","year":"2024","journal-title":"Nature"},{"key":"2026081811105179800_cit31","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/ng.3314","article-title":"The support of human\ngenetic evidence for approved drug indications","volume":"47","author":"Nelson","year":"2015","journal-title":"Nat. Genet."},{"key":"2026081811105179800_cit32","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1172\/JCI30087","article-title":"Intersectin links\nWNK kinases to endocytosis of ROMK1","volume":"117","author":"He","year":"2007","journal-title":"J. Clin.\nInvest."},{"key":"2026081811105179800_cit33","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and\ncomputational approaches to estimate solubility and permeability in\ndrug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv.\nDrug Deliv. Rev."},{"key":"2026081811105179800_cit34","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1186\/ar331","article-title":"Early response\ngenes induced in chondrocytes stimulated\nwith the inflammatory cytokine interleukin-1beta","volume":"3","author":"Vincenti","year":"2001","journal-title":"Arthritis Res."},{"key":"2026081811105179800_cit35","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/1529-0131(200001)43:1&lt;195::AID-ANR24&gt;3.0.CO;2-G","article-title":"Autocrine regulation of collagenase\n3 (matrix metalloproteinase 13) during osteoarthritis","volume":"43","author":"Shlopov","year":"2000","journal-title":"Arthritis Rheum."},{"key":"2026081811105179800_cit36","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1002\/art.1780360107","article-title":"The effect of interleukin-1\non cytokine gene expression in cultured\nhuman articular chondrocytes analyzed by messenger RNA phenotyping","volume":"36","author":"Seid","year":"1993","journal-title":"Arthritis Rheum."},{"key":"2026081811105179800_cit37","doi-asserted-by":"publisher","first-page":"18853","DOI":"10.1038\/s41598-024-69028-9","article-title":"Eriodictyol attenuates\nosteoarthritis progression through inhibiting\ninflammation via the PI3K\/AKT\/NF-kappaB signaling pathway","volume":"14","author":"Kang","year":"2024","journal-title":"Sci. Rep."},{"key":"2026081811105179800_cit38","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202400642R","article-title":"SHP2 ablation mitigates\nosteoarthritic cartilage degeneration by\npromoting chondrocyte anabolism through SOX9","volume":"38","author":"Wang","year":"2024","journal-title":"FASEB J."},{"key":"2026081811105179800_cit39","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1002\/art.41520","article-title":"Familial clustering\nof erosive hand osteoarthritis in a large statewide\ncohort","volume":"73","author":"Kazmers","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"2026081811105179800_cit40","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3109\/03009742.2010.495081","article-title":"Hereditary isolated\nmetatarsophalangeal arthritis","volume":"40","author":"Nissi","year":"2011","journal-title":"Scand. J. Rheumatol."},{"key":"2026081811105179800_cit41","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1136\/annrheumdis-2013-205149","article-title":"A gain of function mutation\nin TNFRSF11B encoding osteoprotegerin\ncauses osteoarthritis with chondrocalcinosis","volume":"74","author":"Ramos","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"2026081811105179800_cit42","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1002\/art.41387","article-title":"Clinical and Molecular\nSpectrum of Nonsyndromic Early-Onset Osteoarthritis","volume":"72","author":"Ruault","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"2026081811105179800_cit43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175474","article-title":"TUFT1, a novel candidate\ngene for metatarsophalangeal osteoarthritis,\nplays a role in chondrogenesis on a calcium-related pathway","volume":"12","author":"Sliz","year":"2017","journal-title":"PLoS One"},{"key":"2026081811105179800_cit44","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2026081811105179800_cit45","doi-asserted-by":"publisher","first-page":"6404","DOI":"10.1038\/s41598-022-10253-5","article-title":"Identification of potent\ninhibitors of NEK7 protein using a comprehensive\ncomputational approach","volume":"12","author":"Aziz","year":"2022","journal-title":"Sci. Rep."},{"key":"2026081811105179800_cit46","doi-asserted-by":"publisher","first-page":"6065","DOI":"10.1021\/acs.jcim.0c00675","article-title":"ZINC20-A Free Ultralarge-Scale Chemical Database\nfor Ligand Discovery","volume":"60","author":"Irwin","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2026081811105179800_cit47","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation\nof fold change\nand dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c04569","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/32\/48157\/66462946\/acsomega.6c04569.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/32\/48157\/66462946\/acsomega.6c04569.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:30:31Z","timestamp":1787074231000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/32\/48157\/5250562\/Identification-and-Validation-of-a-Novel-WNK2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":47,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,7]]},"published-print":{"date-parts":[[2026,8,18]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c04569","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]}}}